Skip to main content Accessibility help
×
Home

Autoimmune Encephalopathies and Epilepsies in Children and Teenagers

  • Lily C. Wong-Kisiel (a1), Andrew McKeon (a2) and Elaine C. Wirrell (a1)

Abstract

Recognition of autoimmune encephalopathies and epilepsies in children and teenagers with acute or subacute onset of central nervous system dysfunction, through detection of the pertinent antibody on serum or cerebral spinal fluid, or through a response to immunotherapy may lead to an early diagnosis, and thus expedited implementation of immunotherapy and improved neurological outcome. The epidemiology of pediatric autoimmune encephalopathy and epilepsy is not well established, but advances in disease-specific biomarker discovery have lead to identification of disorders with either a cytotoxic T cell mediated pathogenesis or (more recently) possible autoantibody mediated disorders. This review summarizes the clinical presentations and recommended evaluations and treatment of pediatric epileptic encephalopathy suspected to be of autoimmune etiology.

    • Send article to Kindle

      To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

      Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

      Find out more about the Kindle Personal Document Service.

      Autoimmune Encephalopathies and Epilepsies in Children and Teenagers
      Available formats
      ×

      Send article to Dropbox

      To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

      Autoimmune Encephalopathies and Epilepsies in Children and Teenagers
      Available formats
      ×

      Send article to Google Drive

      To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

      Autoimmune Encephalopathies and Epilepsies in Children and Teenagers
      Available formats
      ×

Copyright

Corresponding author

Division of Child and Adolescent Neurology, Department of Neurology, Mayo Clinic College of Medicine; 200 First Street, SW; Rochester, Minnesota, 55905, USA.

References

Hide All
1Albert, ML, Darnell, JC, Bender, A, Francisco, LM, Bhardwaj, N, Darnell, RB.Tumor-specific killer cells in paraneoplastic cerebellar degeneration. Nat Med. 1998;4(11):13214.
2Ishiura, H, Matsuda, S, Higashihara, M, et al.Response of anti-NMDA receptor encephalitis without tumor to immunotherapy including rituximab. Neurology. 2008;71(23):19213.
3Lindstrom, JM, Lennon, VA, Seybold, ME, Whittingham, S.Experimental autoimmune myasthenia gravis and myasthenia gravis: biochemical and immunochemical aspects. Ann NY Acad Sci. 1976;274:25474.
4Lennon, VA, Lindstrom, JM, Seybold, ME.Experimental autoimmune myasthenia gravis: cellular and humoral immune responses. Ann N Y Acad Sci. 1976;274:28399.
5Lennon, VA, Ermilov, LG, Szurszewski, JH, Vernino, S.Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. J Clin Invest. 2003; 111(6):90713.
6Vernino, S, Ermilov, LG, Sha, L, Szurszewski, JH, Low, PA, Lennon, VA.Passive transfer of autoimmune autonomic neuropathy to mice. J Neurosci. 2004;24(32):703742.
7Hughes, EG, Peng, X, Gleichman, AJ, et al.Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci. 2010;30(17):586675.
8Constantin, T, Kalovics, T, Ponyi, A, et al.Prevalence of antiphospholipid and antinuclear antibodies in children with epilepsy. Med Sci Monit. 2009;15(4):CR1649.
9Markic, J, Mestrovic, M, Valic, I, Sapunar, A, Bosnjak, N.Frequency of anticardiolipin, antinuclear and anti-beta2 glycoprotein I antibodies in children with epilepsy. Coll Antropol. 2007;31 3: 73942.
10Asadi-Pooya, AA, Asadi-Pooya, K.Antinuclear antibodies in children with epilepsy treated by carbamazepine. Epilepsy Res. 2008;80(23):22930.
11Giordano, L, Valotti, M, Bosetti, A, Accorsi, P, Caimi, L, Imberti, L.Celiac disease-related antibodies in Italian children with epilepsy. Pediatr Neurol. 2009;41(1):346.
12Majoie, HJ, de Baets, M, Renier, W, Lang, B, Vincent, A.Antibodies to voltage-gated potassium and calcium channels in epilepsy. Epilepsy Res. 2006;71(2-3):13541.
13Liimatainen, S, Peltola, M, Sabater, L, et al.Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia. 2010;51(5):7607.
14Pruss, H, Dalmau, J, Harms, L, et al.Retrospective analysis of NMDA receptor antibodies in encephalitis of unknown origin. Neurology. 2010;75(19):17359.
15Bien, CG, Elger, CE.Limbic encephalitis: a cause of temporal lobe epilepsy with onset in adult life. Epilepsy Behav. 2007;10 4: 52938.
16Irani, SR, Buckley, C, Vincent, A, et al.Immunotherapy-responsive seizure-like episodes with potassium channel antibodies. Neurology. 2008;71(20):16478.
17Irani, SR, Michell, AW, Lang, B, et al.Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis. Ann Neurol. 2011;69(5):892900.
18Suleiman, J, Brenner, T, Gill, D, et al.VGKC antibodies in pediatric encephalitis presenting with status epilepticus. Neurology. 2011; 76(14):12525.
19Dhamija, R, Renaud, DL, Pittock, SJ, et al.Neuronal voltage-gated potassium channel complex autoimmunity in children. Pediatr Neurol. 2011;44(4):27581.
20Wainwright, MS, Martin, PL, Morse, RP, et al.Human herpesvirus 6 limbic encephalitis after stem cell transplantation. Ann Neurol. 2001;50(5):6129.
21Duzova, A, Bakkaloglu, A.Central nervous system involvement in pediatric rheumatic diseases: current concepts in treatment. Curr Pharm Des. 2008;14(13):1295301.
22Lie, JT.Primary (granulomatous) angiitis of the central nervous system: a clinicopathologic analysis of 15 new cases and a review of the literature. Hum Pathol. 1992;23(2):16471.
23Castillo, P, Woodruff, B, Caselli, R, et al.Steroid-responsive encephalopathy associated with autoimmune thyroiditis. Arch Neurol. 2006;63(2):197202.
24Chong, JY, Rowland, LP, Utiger, RD.Hashimoto encephalopathy: syndrome or myth? Arch Neurol. 2003;60(2):16471.
25Nolte, KW, Unbehaun, A, Sieker, H, Kloss, TM, Paulus, W.Hashimoto encephalopathy: a brainstem vasculitis? Neurology. 2000;54 3: 76970.
26Grommes, C, Griffin, C, Downes, KA, Lerner, AJ.Steroid-responsive encephalopathy associated with autoimmune thyroiditis presenting with diffusion MR imaging changes. AJNR Am J Neuroradiol. 2008;29(8):15501.
27Ferracci, F, Bertiato, G, Moretto, G.Hashimoto’s encephalopathy: epidemiologic data and pathogenetic considerations. J Neurol Sci. 2004;217(2):1658.
28Gayatri, NA, Whitehouse, WP.Pilot survey of Hashimoto’s encephalopathy in children. Dev Med Child Neurol. 2005;47 8: 5568.
29Watemberg, N, Greenstein, D, Levine, A.Encephalopathy associated with Hashimoto thyroiditis: Pediatric perspective. J Child Neurol. 2006;21(1):15.
30Vasconcellos, E, Pina-Garza, JE, Fakhoury, T, Fenichel, GM.Pediatric manifestations of Hashimoto’s encephalopathy. Pediatr Neurol. 1999;20(5):3948.
31Maki, M, Mustalahti, K, Kokkonen, J, et al.Prevalence of celiac disease among children in Finland. N Engl JMed. 2003;348 25: 251724.
32Cook, HB, Burt, MJ, Collett, JA, Whitehead, MR, Frampton, CM, Chapman, BA.Adult coeliac disease: prevalence and clinical significance. J Gastroenterol Hepatol. 2000;15(9):10326.
33Chapman, RW, Laidlow, JM, Colin-Jones, D, Eade, OE, Smith, CL.Increased prevalence of epilepsy in coeliac disease. Br Med J. 1978;2(6132):2501.
34Pengiran Tengah, DSHolmes, GKWills, AJ.The prevalence of epilepsy in patients with celiac disease. Epilepsia. 2004;45 10: 12913.
35Hanly, JG, Stassen, W, Whelton, M, Callaghan, N.Epilepsy and coeliac disease. J Neurol Neurosurg Psychiatry. 1982;45(8):72930.
36Zelnik, N, Pacht, A, Obeid, R, Lerner, A.Range of neurologic disorders in patients with celiac disease. Pediatrics. 2004;113 6: 16726.
37Ruggieri, M, Incorpora, G, Polizzi, A, Parano, E, Spina, M, Pavone, P.Low prevalence of neurologic and psychiatric manifestations in children with gluten sensitivity. J Pediatr. 2008;152(2):2449.
38Lionetti, E, Francavilla, R, Pavone, P, et al.The neurology of coeliac disease in childhood: what is the evidence? a systematic review and meta-analysis. Dev Med Child Neurol. 2010;52(8):7007.
39Arroyo, HA, De Rosa, S, Ruggieri, V, de Davila, MT, Fejerman, N.Epilepsy, occipital calcifications, and oligosymptomatic celiac disease in childhood. J Child Neurol. 2002;17(11):8006.
40Gobbi, G.Coeliac disease, epilepsy and cerebral calcifications. Brain Dev. 2005;27(3):189200.
41Benseler, SM, Silverman, ED.Neuropsychiatric involvement in pediatric systemic lupus erythematosus. Lupus. 2007;16 8: 56471.
42Tan, KM, Lennon, VA, Klein, CJ, Boeve, BF, Pittock, SJ.Clinical spectrum of voltage-gated potassium channel autoimmunity. Neurology. 2008;70(20):188390.
43Vincent, A, Buckley, C, Schott, JM, et al.Potassium channel antibody-associated encephalopathy: a potentially immuno-therapy-responsive form of limbic encephalitis. Brain. 2004;127 (Pt 3):70112.
44Geschwind, MD, Tan, KM, Lennon, VA, et al.Voltage-gated potassium channel autoimmunity mimicking Creutzfeldt-Jakob disease. Arch Neurol. 2008;65(10):13416.
45Schulte, U, Thumfart, JO, Klocker, N, et al.The epilepsy-linked Lgi1 protein assembles into presynaptic Kv1 channels and inhibits inactivation by Kvbeta1. Neuron. 2006;49(5):697706.
46Ogawa, Y, Oses-Prieto, J, Kim, MY, et al.Adam22, a Kv1 channel-interacting protein, recruits membrane-associated guanylate kinases to juxtaparanodes of myelinated axons. J Neurosci. 2010;30(3):103848.
47Lai, M, Huijbers, MG, Lancaster, E, et al.Investigation of Lgi1 as the antigen in limbic encephalitis previously attributed to potassium channels: a case series. Lancet Neurol. 2010;9(8):77685.
48Irani, SR, Alexander, S, Waters, P, et al.Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010; 133(9):273448.
49Kroll-Seger, J, Bien, CG, Huppertz, HJ.Non-paraneoplastic limbic encephalitis associated with antibodies to potassium channels leading to bilateral hippocampal sclerosis in a pre-pubertal girl. Epileptic Disord. 2009;11(1):549.
50Haberlandt, E, Bast, T, Ebner, A, et al.Limbic encephalitis in children and adolescents. Arch Dis Child. 2011; 96(2):18691.
51Dalmau, J, Lancaster, E, Martinez-Hernandez, E, Rosenfeld, MR, Balice-Gordon, R.Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol. 2011; 10(1):6374.
52Dalmau, J, Gleichman, AJ, Hughes, EG, et al.Anti-NMDA-receptor encephalitis: Case series and analysis of the effects of antibodies. Lancet Neurol. 2008;7(12):10918.
53Dale, RC, Irani, SR, Brilot, F, et al.N-methyl-d-aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica. Ann Neurol. 2009;66(5):7049.
54Florance, NR, Davis, RL, Lam, C, et al.Anti-n-methyl-d-aspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol. 2009;66(1):118.
55Irani, SR, Bera, K, Waters, P, et al.N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain. 2010;133(Pt 6):165567.
56Niehusmann, P, Dalmau, J, Rudlowski, C, et al.Diagnostic value of n-methyl-d-aspartate receptor antibodies in women with new-onset epilepsy. Arch Neurol. 2009;66(4):45864.
57Dalmau, J, Tuzun, E, Wu, HY, et al.Paraneoplastic anti-n-methyl-daspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61(1):2536.
58Lennon, VA, Wingerchuk, DM, Kryzer, TJ, et al.A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):210612.
59McKeon, A, Lennon, VA, Lotze, T, et al.CNS aquaporin-4 autoimmunity in children. Neurology. 2008;71(2):93100.
60Lotze, TE, Northrop, JL, Hutton, GJ, Ross, B, Schiffman, JS, Hunter, JV.Spectrum of pediatric neuromyelitis optica. Pediatrics. 2008; 122(5):e103947.
61Lai, M, Hughes, EG, Peng, X, et al.AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol. 2009;65(4):42434.
62Lancaster, E, Lai, M, Peng, X, et al.Antibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010; 9(1):6776.
63Graus, F, Keime-Guibert, F, Rene, R, et al.Anti-Hu-associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124(Pt 6):113848.
64Antunes, NL, Khakoo, Y, Matthay, KK, et al.Antineuronal antibodies in patients with neuroblastoma and paraneoplastic opsoclonus-myoclonus. J Pediatr Hematol Oncol. 2000;22(4):31520.
65Saiz, A, Bruna, J, Stourac, P, et al.Anti-Hu-associated brainstem encephalitis. J Neurol Neurosurg Psychiatry. 2009;80(4):4047.
66Voltz, R, Gultekin, SH, Rosenfeld, MR, et al.A serologic marker of paraneoplastic limbic and brain-stem encephalitis in patients with testicular cancer. N Engl J Med. 1999;340(23):178895.
67Dalmau, J, Gultekin, SH, Voltz, R, et al.Ma1, a novel neuron- and testis-specific protein, is recognized by the serum of patients with paraneoplastic neurological disorders. Brain. 1999;122(Pt 1):2739.
68Pittock, SJ, Yoshikawa, H, Ahlskog, JE, et al.Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Mayo Clin Proc. 2006;81 9: 120714.
69Liimatainen, S, Peltola, M, Sabater, L, et al.Clinical significance of glutamic acid decarboxylase antibodies in patients with epilepsy. Epilepsia. 2010;51(5):7607.
70Moersch, FP, Woltman, HW.Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin. 1956;31(15):4217.
71Saiz, A, Blanco, Y, Sabater, L, et al.Spectrum of neurological syndromes associated with glutamic acid decarboxylase antibodies: diagnostic clues for this association. Brain. 2008;131 (Pt 10):255363.
72Bingley, PJ, Bonifacio, E, Williams, AJ, Genovese, S, Bottazzo, GF, Gale, EA.Prediction of IDDM in the general population: strategies based on combinations of autoantibody markers. Diabetes. 1997;46(11):170110.
73Bingley, PJ.Clinical applications of diabetes antibody testing. J Clin Endocrinol Metab. 95(1):2533.
74Verrotti, A, Greco, R, Altobelli, E, Latini, G, Morgese, G, Chiarelli, F.Anticardiolipin, glutamic acid decarboxylase, and antinuclear antibodies in epileptic patients. Clin Exp Med. 2003;3(1):326.
75Peltola, J, Kulmala, P, Isojarvi, J, et al.Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy. Neurology. 2000;55(1):4650.
76McKnight, K, Jiang, Y, Hart, Y, et al.Serum antibodies in epilepsy and seizure-associated disorders. Neurology. 2005;65(11):17306.
77Errichiello, L, Perruolo, G, Pascarella, A, et al.Autoantibodies to glutamic acid decarboxylase (GAD) in focal and generalized epilepsy: a study on 233 patients. J Neuroimmunol. 2009;211(12):1203.
78Mata, S, Muscas, GC, Naldi, I, et al.Non-paraneoplastic limbic encephalitis associated with anti-glutamic acid decarboxylase antibodies. J Neuroimmunol. 2008;199(1-2):1559.
79Malter, MP, Helmstaedter, C, Urbach, H, Vincent, A, Bien, CG.Antibodies to glutamic acid decarboxylase define a form of limbic encephalitis. Ann Neurol. 2010;67(4):4708.
80Rasmussen, T, Olszewski, J, Lloydsmith, D.Focal seizures due to chronic localized encephalitis. Neurology. 1958;8(6):43545.
81Rogers, SW, Andrews, PI, Gahring, LC, et al.Autoantibodies to glutamate receptor GluR3 in Rasmussen’s encephalitis. Science. 1994;265(5172):64851.
82Watson, R, Jiang, Y, Bermudez, I, et al.Absence of antibodies to glutamate receptor type 3 (GluR3) in Rasmussen encephalitis. Neurology. 2004;63(1):4350.
83Schwab, N, Bien, CG, Waschbisch, A, et al.CD8+ T cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery. Brain. 2009;132(Pt 5):123646.
84Granata, T, Fusco, L, Gobbi, G, et al.Experience with immunomodulatory treatments in Rasmussen’s encephalitis. Neurology. 2003;61(12):180710.
85Quek, AML, Britton, J, McKeon, A, et al.Autoimmune epilepsy: retrospective analysis of 26 patients. Neurology 2011; 76:A356.
86McKeon, A, Lennon, VA, Pittock, SJ.Immunotherapy-responsive dementias and encephalopathies. Continuum Lifelong Learning Neurol. 2010;16(2):80101.
87Pittock, SJ, Kryzer, TJ, Lennon, VA.Paraneoplastic antibodies coexist and predict cancer, not neurological syndrome. Ann Neurol. 2004;56(5):7159.
88Davidoff, AM.Pediatric oncology. Semin Pediatr Surg. 2010;19 3: 22533.
89Murphy, JJ, Tawfeeq, M, Chang, B, Nadel, H.Early experience with PET/CT scan in the evaluation of pediatric abdominal neoplasms. J Pediatr Surg. 2008;43(12):218692.
90McKeon, A, Apiwattanakul, M, Lachance, DH, et al.Positron emission tomography-computed tomography in paraneoplastic neurologic disorders: systematic analysis and review. Arch Neurol. 2010; 67(3):3229.
91Kuntz, NL, Chabas, D, Weinstock-Guttman, B, et al.Treatment of multiple sclerosis in children and adolescents. Expert Opin Pharmacother. 2010; 11(4):50520.
92Recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update. American College of Rheumatology Ad Hoc Committee on glucocorticoid-induced osteoporosis. Arthritis Rheum. 2001;44 7: 1496503.
93Wagner, CL, Greer, FR.Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008; 122(5):114252.
94Schimmer, BP, Parker, KL.Adrenocorticotropic hormone; adrenocortical steroid and their synthetic analogs; inhibitors of the synthesis and action of adrenocortical hormones. In: Hardman, JG, Limbird, LE, editors. Goodman and Gilman’s the pharmacological basis of therapeutics 10th Ed. New York: McGraw-Hill; 2001. p. 1657.
95Wong-Kisiel, LC, Ji, T, Renaud, DL, et al.Response to immunotherapy in a 20-month-old boy with anti-NMDA receptor encephalitis. Neurology. 2010;74(19):15501.
96Rosenfeld, MR, Eichen, JG, Wade, DF, Posner, JB, Dalmau, J.Molecular and clinical diversity in paraneoplastic immunity to Ma proteins. Ann Neurol. 2001;50(3):33948.
97Vernino, S, O’Neill, BP, Marks, RS, O’Fallon, JR, Kimmel, DW.Immunomodulatory treatment trial for paraneoplastic neurological disorders. Neuro Oncol. 2004;6(1):5562.
98Flanagan, EP, McKeon, A, Lennon, VA, et al.Autoimmune dementia: Clinical course and predictors of immunotherapy response. Mayo Clin Proc. 2010; 85(10):88197.

Metrics

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed